, 2006). These

discrepancies within the literature may be due to differences in the pain test or animal species used and also due to the inability of ligands used in earlier studies to sufficiently discriminate between 5-HT2A and 5-HT2C receptors. The 5-HT2C receptor is present in the dorsal horn of the spinal cord, with 5-HT2C receptor mRNA expressed at high levels in most of the grey matter, except for lamina II (Fonseca et al., 2001). This receptor subtype is likely to have a predominant postsynaptic localization, since 5-HT2C mRNA was undetected in naïve rat DRG (Nicholson et al., 2003 and Wu et Tyrosine Kinase Inhibitor Library al., 2001) but are expressed de novo in rat DRG after inflammation ( Wu et al., 2001). The 5-HT2C receptor shares similar pharmacological and transductional features with the 5-HT2A receptor; however, with regards to modulation of spinal nociceptive transmission, a number of recent studies

have assigned an antinociceptive role for this receptor subtype. For example, intrathecal administration of selective 5-HT2C receptor agonists attenuated pain-related behaviour in a rat model of trigeminal and spinal nerve ligated model of neuropathic pain, which may involve activation of spinal noradrenergic mechanisms ( Nakai et al., 2010, Obata et al., 2004 and Obata et al., 2007). Activation of spinal 5-HT2C Docetaxel nmr receptors was also shown to reduce the C-fibre evoked spinal field potentials in spinal nerve ligated and sham control rats ( Aira et al., 2010), and why the selective 5-HT2C receptor antagonist RS 102221 reversed the inhibitory effect of spinal 5-HT on the evoked response of dorsal horn wide dynamic range neurons ( Liu et al., 2007). The 5-HT2

receptors have a very high amino-acid sequence homology and thus many compounds have an affinity for all three subtypes. Despite the selectivity limitations of drugs targeting 5-HT2 receptors, the emerging consensus, from the studies discussed above, points to a pronociceptive role for the 5-HT2A (Eide and Hole, 1991, Kjorsvik et al., 2001, Nishiyama, 2005, Silveira et al., 2010 and Thibault et al., 2008) but see (Honda et al., 2006, Sasaki et al., 2001 and Sasaki et al., 2003) and an antinociceptive role for the 5-HT2C receptor subtypes in modulating spinal nociceptive transmission (Aira et al., 2010, Liu et al., 2007, Obata et al., 2004 and Obata et al., 2007). Our findings in the present study demonstrate a clear pronociceptive role for spinal 5-HT2 receptors, most likely through targeting the 5-HT2A receptor subtype since the selective 5-HT2A antagonist ketanserin inhibited evoked neuronal responses, and in particular, inhibited the noxious evoked natural mechanical and thermal stimuli. Although ketanserin is the prototypical antagonist for 5-HT2A receptors, it also has affinity, but at higher concentrations, for the 5-HT2C receptor.